The present invention relates to tricyclic compounds, namely, substituted isoquinolines, isochromanones and isothiochromanones that inhibit the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and/or interleukin-6 (IL-6) and/or the enzyme cyclooxygenase-2 (COX-2) and/or the cytokine interleukin-10 (IL-10). This invention also relates to compositions containing such compounds and methods using such compounds for treatment and/or prevention of inflammation, inflammatory diseases, immunologic diseases and other diseases mediated by TNF-alpha, IL-6, IL-10 and/or COX-2.
The present invention is concerned with the modulation of cellular signaling pathways involving pro-inflammatory cytokines and cyclooxygenase-2 (COX-2). Cytokines are molecules secreted by immune cells that are important in mediating immune responses. Cytokine production may lead to the secretion of other cytokines, altered cellular function, cell division or differentiation. Inflammation is the body""s normal response to injury or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathologic inflammatory processes can lead to morbidity and mortality. The cytokine tumor necrosis factor-alpha (TNF-alpha) plays a central role in the inflammatory response and has been targeted as a point of intervention in inflammatory disease. TNF-alpha is a polypeptide hormone released by activated macrophages and other cells. At low concentrations, TNF-alpha participates in the protective inflammatory response by activating leukocytes and promoting their migration to extravascular sites of inflammation (Moser et al., J Clin Invest, 83:444-55, 1989). At higher concentrations, TNF-alpha can act as a potent pyrogen and induce the production of other pro-inflammatory cytokines (Haworth et al., Eur J Immunol, 21:2575-79, 1991; Brennan et al., Lancet, 2:244-7, 1989). TNF-alpha also stimulates the synthesis of acute-phase proteins. In rheumatoid arthritis, a chronic and progressive inflammatory disease affecting about 1% of the adult U.S. population, TNF-alpha mediates the cytokine cascade that leads to joint damage and destruction (Arend et al, Arthritis Rheum, 38:151-60, 1995). Inhibitors of TNF-alpha, including soluble TNF receptors (etanercept) (Goldenberg, Clin Ther, 21:75-87,1999) and anti-TNF-alpha antibody (infliximab) (Luong et al, Ann Pharmacother, 34:743-60, 2000), have recently been approved by the U.S. Food and Drug Administration (FDA) as agents for the treatment of rheumatoid arthritis.
Elevated levels of TNF-alpha have also been implicated in many other disorders and disease conditions, including cachexia (Fong et al., Am J Physiol, 256:R659-65, 1989), septic shock syndrome (Tracey et al, Proc Soc Exp Biol Med, 200:233-9, 1992), osteoarthritis (Venn et al., Arthritis Rheum, 36:819-26, 1993), inflammatory bowel disease such as Crohn""s disease and ulcerative colitis (Murch et al., Gut, 32:913-7, 1991), Behcet""s disease (Akoglu et al., J Rheumatol, 17:1107-8,1990), Kawasaki disease (Matsubara et al., Clin Immunol Immunopathol, 56:29-36, 1990), cerebral malaria (Grau et al., N Engl J Med, 320:1586-91, 1989), adult respiratory distress syndrome (Millar et al., Lancet, 2:712-4, 1989), asbestosis and silicosis (Bissonnette et al., Inflammation, 13:329-39, 1989), pulmonary sarcoidosis (Baughman et al., J Lab Clin Med, 115:36-42, 1990), asthma (Shah et al., Clin Exp Allergy, 25:1038-44,1995), AIDS (Dezube et al., J Acquir Immune Defic Syndr, 5:1099-104, 1992), meningitis (Waage et al., Lancet, 1:355-7,1987), psoriasis (Oh et al., J Am Acad Dermatol, 42:829-30, 2000), graft versus host reaction (Nestel et al., J Exp Med, 175:405-13, 1992), multiple sclerosis (Sharief et al., N Engl J Med, 325:467-72,1991), systemic lupus erythematosus (Maury et al., Int J Tissue React, 11:189=93, 1989), and diabetes (Hotamisligil et al., Science, 259:87-91, 1993).
It can be seen from the references cited above that inhibitors of TNF-alpha are potentially useful in the treatment of a wide variety of diseases. Compounds that inhibit TNF-alpha have been described in U.S. Pat. Nos. 6,090,763; 6,080,580; 6,075,041; 6,057,369; 6,048,841; 6,046,319; 6,046,221; 6,040,329; 6,034,100; 6,028,086; 6,022,884; 6,015,558; 6,004,974; 5,990,119; 5,981,701; 5,977,122; 5,972,936; 5,968,945; 5,962,478; 5,958,953; 5,958,409; 5,955,480; 5,948,786; 5,935,978; 5,935,977; 5,929,117; 5,925,636; 5,900,430; 5,900,417; 5,891,883; 5,869,677 and others.
Interleukin-6 (IL-6) is another pro-inflammatory cytokine that exhibits pleiotropy and redundancy of action. IL-6 participates in the immune response, inflammation and hematopoiesis. It is a potent inducer of the hepatic acute phase response and is a powerful stimulator of the hypothalamic-pituitary-adrenal axis that is under negative control by glucocorticoids. IL-6 promotes the secretion of growth hormone but inhibits release of thyroid stimulating hormone. Elevated levels of IL-6 are seen in several inflammatory diseases, and inhibition of the IL-6 cytokine subfamily has been suggested as a strategy to improve therapy for rheumatoid arthritis (Carroll et al., Inflamm Res, 47:1-7,1998). In addition, IL-6 has been implicated in the progression of atherosclerosis and the pathogenesis of coronary heart disease (Yudkin et al., Atherosclerosis, 148:209-14, 1999). Overproduction of IL-6 is also seen in steroid withdrawal syndrome, conditions related to deregulated vasopressin secretion, and osteoporosis associated with increased bone resorption, such as in cases of hyperparathyroidism and sex-steroid deficiency (Papanicolaou et al., Ann Intern Med, 128:127-37, 1998).
Since excessive production of IL-6 is implicated in several disease states, it is highly desirable to develop compounds that inhibit IL-6 secretion. Compounds that inhibit IL-6 have been described in U.S. Pat. Nos. 6,004,813; 5,527,546 and 5,166,137.
Cyclooxygenase is an enzyme that catalyzes a rate-determining step in the biosynthesis of prostaglandins, which are important mediators of inflammation and pain. The enzyme occurs as at least two distinct isomers, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The COX-1 isomer is constitutively expressed in the gastric mucosa, platelets and other cells and is involved in the maintenance of homeostasis in mammals, including protecting the integrity of the digestive tract. The COX-2 isomer, on the other hand, is not constitutively expressed but rather is induced by various agents, such as cytokines, mitogens, hormones and growth factors. In particular, COX-2 is induced during the inflammatory response (DeWitt DL, Biochim Biophys Acta, 1083:121-34, 1991; Seibert et al., Receptor, 4:17-23, 1994). Aspirin and other conventional non-steroid anti-inflammatory drugs (NSAIDs) are non-selective inhibitors of both COX-1 and COX-2. They can be effective in reducing inflammatory pain and swelling, but since they hamper the protective action of COX-1, they produce undesirable side effects of gastrointestinal pathology. Therefore, agents that selectively inhibit COX-2 but not COX-1 are preferable for treatment of inflammatory diseases. Recently, a diarylpyrazole sulfonamide (celecoxib) that specifically blocks COX-2 has been approved by the FDA for use in the treatment of rheumatoid arthritis (Luong et al., Ann Pharmacother, 34:743-60, 2000; Penning et al., J Med Chem, 40:1347-65, 1997). COX-2 is also expressed in many cancers and precancerous lesions, and there is mounting evidence that selective COX-2 inhibitors may be useful for treating and preventing colorectal and other cancers (Taketo MM, J Natl Cancer Inst, 90:1609-20, 1998; Fournier et al., J Cell Biochem Suppl, 34:97-102, 2000). In 1999, celecoxib was approved by the FDA as an adjunct to usual care for patients with familial adenomatous polyposis, a condition which, left untreated, generally leads to colorectal cancer.
Compounds that selectively inhibit COX-2 have been described in U.S. Pat. Nos. 5,344,991; 5,380,738; 5,434,178; 5,466,823; 5,474,995; 5,510,368; 5,521,207; 5,521,213; 5,536,752; 5,550,142; 5,552,422; 5,604,260; 5,639,780; 5,643,933; 5,677,318; 5,691,374; 5,698,584; 5,710,140; 5,733,909; 5,789,413; 5,811,425; 5,817,700; 5,849,943; 5,859,257; 5,861,419; 5,905,089; 5,922,742; 5,925,631; 5,932,598; 5,945,539; 5,968,958; 5,981,576; 5,994,379; 5,994,381; 6,001,843; 6,002,014; 6,004,950; 6,004,960; 6,005,000; 6,020,343; 6,034,256; 6,046,191; 6,046,217; 6,057,319; 6,071,936; 6,071,954; 6,077,850; 6,077,868; 6,077,869 and 6,083,969.
The immunoregulatory cytokine interleukin-10 (IL-10) is a potent down-regulator of specific pro-inflammatory cytokines, but its role in inflammatory diseases and immune disorders is complex. Administration or overexpression of IL-10 is believed in many cases to counterbalance the action of pro-inflammatory cytokines and therefore to ameliorate inflammatory disease (Verhoef et al, J Rheumatol, 28:1960-6, 2001; McInnes et al, J Immunol, 167:4075-82, 2001; Lamblin et al, J Allergy Clin Immunol, 107:739-41, 2001; Cook et al, Am Surg, 67:237-41, 2001). In other cases, paradoxically, production or overexpression of IL-10 has been correlated with the promotion of inflammatory diseases or immune disorders, including systemic lupus erythematosus (Alarcon-Segovia, Isr Med Assoc J, 3:127-30, 2001; Bussolati et al, Clin Exp Immunol 122:471-6, 2000; Gonzalez-Amaro et al, J Autoimmun, 11:395-402,1998; Kalechman et al, J Immunol, 159:2658-67, 1997; Mongan et al, Scand J Immunol 46:406-12, 1997; Houssiau et al, Lupus 4:393-5, 1995), multiple sclerosis (Nakashima et al, J Neuroimmunol, 111:64-7, 2000; Navikas et al, Scand J Immunol, 41:171-8, 1995), myasthenia gravis (Ostlie et al, J Immunol, 166:4853-62, 2001; Huang et al, Clin Exp Immunol, 118:304-8,1999) and arthritis (Johansson et al, J Immunol, 167:3505-12, 2001).
Since elevated levels of IL-10 are associated with several disease states, compounds that inhibit IL-10 have potential therapeutic utility. Compositions and methods for inhibition of IL-10 have been described in U.S. Pat. Nos. 6,251,878; 6,239,260; 6,207,154; 6,184,372; 6,184,246 and 5,837,232.
It can be understood from the above discussions that a compound which inhibits both COX-2 and the pro-inflammatory cytokines TNF-alpha and IL-6 would be highly desirable for its potential use in treating diseases mediated by these agents, particularly inflammatory diseases such as rheumatoid arthritis and the like. It will also be apparent that compounds that inhibit IL-10 are desirable for their potential use in treating similar diseases, particularly autoimmune disorders.
Alkaloids such as sinomenine (Liu et al., Int J Immunopharmacol, 18:529-43, 1996), bukittinggine (Panthong et al., Planta Med, 64:530-5, 1998), tetrandine and berbamine (Wong et al., Agents Actions, 36:112-8, 1992) are well known for their anti-inflammatory activities. Isoquinoline derivatives with demonstrated or potential anti-inflammatory properties have also been described (van Muijlwijk-Koezen et al., J Med Chem, 43:2227-38, 2000; Xu et al., J Nat Prod, 62:1025-7, 1999; Chao et al., J Med Chem, 42:3860-73,1999; van Muijlwijk-Koezen et al., J Med Chem, 41:3987-93, 1998; van Muijlwijk-Koezen et al., J Med Chem, 41:3994-4000, 1998). Disease-modifying anti-rheumatic drugs (DMARDS) based on quinoline and related structures are also known (Baba et al., Chem Pharm Bull [Tokyo], 47:993-9,1999; Baba et al., J Med Chem, 39:5176-82, 1996). Berberine is an isoquinoline alkaloid that occurs naturally in plants belonging to the Berberidaceae and Ranunculaceae families. Extracts from these plants have been used for centuries in Eastern folk medicine as remedies for inflammation and hypertension. The anti-inflammatory effects of berberine and berberine-containing extracts have also been demonstrated in animal models (Ivanovska et al., Int J Immunopharmacol, 18:553-61, 1996; Yasukawa et al., Chem Pharm Bull [Tokyo], 39:1462-5,1991; Zhang et al., Chung Kuo Yao Li Hsueh Pao, 10:174-6,1989; Akhter et al., Indian J Med Res, 65:133-41, 1977) and in vitro studies (Ckless et al., J Pharm Pharmacol, 47:1029-31, 1995). The present invention describes novel substituted isoquinolines chemically distinct from, but having some structural features similar to, native berberine.
The present invention is directed to compounds that inhibit the production and/or activity of the pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-6, the enzyme cyclooxygenase-2 and/or interleukin-10, and therefore are useful for the prevention and/or treatment of inflammation, inflammatory diseases, immunologic diseases, autoimmune disorders and other diseases mediated by these agents. In particular, the subject invention discloses substituted isoquinolines of Formulas I-IV, isochromanones of Formulas V-VII, and isothiochromanones of Formulas VIII-X as well as the pharmaceutically acceptable salts and solvates thereof: 
wherein the stereocenters marked with an asterisk (*) may be Rxe2x80x94 or Sxe2x80x94 and
R1, R2, R3, R4, R5 and R6 are independently
H; optionally substituted C1-C20 linear or branched alkyl including chloroalkyl or fluoroalkyl; optionally substituted C2-C20 linear or branched alkenyl; optionally substituted C6-C20 aryl, linear or branched alkylaryl, linear or branched alkenylaryl; COOR where R is H, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl, sodium, potassium or other pharmaceutically acceptable counter-ion such as calcium, magnesium, ammonium, tromethamine and the like; CONRxe2x80x2Rxe2x80x3, where Rxe2x80x2 and Rxe2x80x3 are independently H, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl or where NRxe2x80x2Rxe2x80x3 represents a cyclic moiety such as morpholine, piperidine, piperazine and the like; NH2; optionally substituted C1-C20 alkylamino, bis(alkylamino), cycloalkylamino or cyclic amino; OH; optionally substituted C1-C20 alkoxy, including trifluoromethoxy, and the like; optionally substituted C1-C20 alkanoyl; optionally substituted C1-C20 acyloxy; halo; optionally substituted C1-C20 alkylcarboxylamino; cyano; nitro; SO2NRxe2x80x2xe2x80x3Rxe2x80x3xe2x80x3 where Rxe2x80x2xe2x80x3 and Rxe2x80x3xe2x80x3 are independently H, C1-C20 alkyl or aryl; SO2Rxe2x80x2xe2x80x3 where Rxe2x80x2xe2x80x3 is H, C1-C20 alkyl or aryl; SO3Rxe2x80x2xe2x80x3where Rxe2x80x2xe2x80x3 is H, C1-C20 alkyl or aryl; or C4-C8 heterocycles such as tetrazolyl, imidazolyl, pyrrolyl, pyridyl, indolyl and the like; or when individual aromatic rings possess adjacent substituents, these substituents may be joined to form a ring such as a methylenedioxy or ethylenedioxy group, and the like, including lactones and lactams;
R7 is
H (in which case the compounds may be in tautomeric form) or optionally substituted C1-C20 linear or branched alkyl including chloroalkyl or fluoroalkyl;
R8 is
H; OH (or O in the case of Formula I); optionally substituted C1-C20 linear or branched alkyl including chloroalkyl or fluoroalkyl; optionally substituted C2-C20 linear or branched alkenyl; optionally substituted C6-C20 aryl, linear or branched alkylaryl, linear or branched alkenylaryl; COOR where R is H, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl, sodium, potassium or other pharmaceutically acceptable counter-ion such as calcium, magnesium, ammonium, tromethamine and the like; CONRxe2x80x2Rxe2x80x3, where Rxe2x80x2 and Rxe2x80x3 are independently H, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl or where NRxe2x80x2Rxe2x80x3 represents a cyclic moiety such as morpholine, piperidine, piperazine and the like; or optionally substituted alkanoyl, alkenoyl, aroyl, alkylaroyl or alkenylaroyl; and xe2x80x9cAxe2x88x92xe2x80x9d represents a pharmaceutically acceptable counter-ion such as chloride, sulfate, phosphate, acetate and the like; or R8 is absent, in which case the nitrogen does not bear a positive charge and the counter-ion xe2x80x9cAxe2x88x92xe2x80x9d is not present;
Y and Yxe2x80x2 are independently
H; optionally substituted C1-C20 linear or branched alkyl including chloroalkyl or fluoroalkyl; optionally substituted C2-C20 linear or branched alkenyl; optionally substituted C6-C20 aryl, linear or branched alkylaryl, linear or branched alkenylaryl; COOR where R is H, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl, sodium, potassium or other pharmaceutically acceptable counter-ion such as calcium, magnesium, ammonium, tromethamine and the like; CONRxe2x80x2Rxe2x80x3, where Rxe2x80x2 and Rxe2x80x3 are independently H, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl or where NRxe2x80x2Rxe2x80x3 represents a cyclic moiety such as morpholine, piperidine, piperazine and the like; NH2; optionally substituted C1-C20 alkylamino, bis(alkylamino), cycloalkylamino or cyclic amino; OH; optionally substituted C1-C20 alkoxy, including trifluoromethoxy, and the like; optionally substituted C1-C20 alkanoyl; optionally substituted C1-C20 acyloxy; halo; optionally substituted C1-C20 alkylcarboxylamino; cyano; nitro; SO2NRxe2x80x2xe2x80x3Rxe2x80x3xe2x80x3 where Rxe2x80x2xe2x80x3 and Rxe2x80x3xe2x80x3 are independently H, C1-C20 alkyl or aryl; SO2Rxe2x80x2xe2x80x3 where Rxe2x80x2xe2x80x3 is H, C1-C20 alkyl or aryl; SO3Rxe2x80x2xe2x80x3 where Rxe2x80x2xe2x80x3 is H, C1-C20 alkyl or aryl; or C4-C8 heterocycles such as tetrazolyl, imidazolyl, pyrrolyl, pyridyl, indolyl and the like; or Y and Yxe2x80x2 together may be joined in a ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, including heterocycles such as lactones, lactams and the like;
Z is
OH; optionally substituted C1-C20 alkoxy, including trifluoromethoxy, and the like; NRxe2x80x2Rxe2x80x3, where Rxe2x80x2 and Rxe2x80x3 are independently H, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl or where NRxe2x80x2Rxe2x80x3 represents a cyclic moiety such as morpholine, piperidine, piperazine and the like; or SRxe2x80x2xe2x80x3xe2x80x3 where Rxe2x80x2xe2x80x3xe2x80x3 is H, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl;
Zxe2x80x2 is
O; S; or NRxe2x80x2xe2x80x3xe2x80x3, where Rxe2x80x2xe2x80x3xe2x80x3 is H, optionally substituted C1-C20 alkyl, optionally substituted C2-C20 alkenyl or optionally substituted C6-C10 aryl;
with the provisos that in Formula I,
when Y is H, then Z is OH, R8 is H, and R1, R2 and R3 are not 6-methoxy; when Y is methyl or substituted benzyl, then R1, R2 and R3 do not comprise 6,7-dimethoxy or 5,6,7-trimethoxy or 6,7,8-trimethoxy; and when Z is OH, at least one of R1, R2, R3, R4, R5 and R6 is not H;
in Formula II,
when Y is H and Yxe2x80x2 is H, then Zxe2x80x2 is O, R8 is H, and R1, R2 and R3 are not 6-methoxy;
when Y is H and Yxe2x80x2 is methyl or substituted benzyl, then R1, R2 and R3 do not comprise 6,7-dimethoxy or 5,6,7-trimethoxy or 6,7,8-trimethoxy; and
when Zxe2x80x2 is O, at least one of R1, R2, R3, R4, R5, R6 and R7 is not H;
in Formula III,
when Y is H and Yxe2x80x2 is H, then Z is OH, R8 is H, and R1, R2 and R3 are not 6-methoxy;
when Y is H and Yxe2x80x2 is methyl or substituted benzyl, then
R1, R2 and R3 do not comprise 6,7-dimethoxy or 5,6,7-trimethoxy or 6,7,8-trimethoxy; and
when Z is OH or alkoxy, at least one of R1, R2, R3, R4, R5 and R6 is not H;
in Formula IV,
when Y is H and Yxe2x80x2 is H, then Z is OH, R8 is H, and R1, R2 and R3 are not 6-methoxy;
when Y is H and Yxe2x80x2 is methyl or substituted benzyl, then
R1, R2 and R3 do not comprise 6,7-dimethoxy or 5,6,7-trimethoxy or 6,7,8-trimethoxy; and
when Z is OH, at least one of R1, R2, R3, R4, R5 and R6 is not H;
in Formula V,
when Zxe2x80x2 is and Y and/or Yxe2x80x2 is phenyl, then at least one of R1, R2, R3, R4, R5 and R6 is not Hxe2x80x2
when Zxe2x80x2 is O and Y and/or Yxe2x80x2 is alkoxy, then R, R5 and R6 are not aminoethyl; and
when Zxe2x80x2 is O and Y is H and Yxe2x80x2 is H, then R1 is not H;
in Formula VI,
when Z is OH and Y and/or Yxe2x80x2 is phenyl, then at least one of R1, R2, R3, R4, R5 and R6 is not H;
in Formula VII,
when Z is methyl or phenyl, then at least one of R1, R2, R3, R4, R5, R6 and R7is not H;
when Z is OH and Y and/or Yxe2x80x2 is phenyl, then at least one of R1, R2, R3, R4, R5 and R6 is not H;
when Z is OH and Y and/or Yxe2x80x2 is alkoxy, then R4, R5 and R6 are not aminoethyl; and
when Z is OH and Y is H and Yxe2x80x2 is H, then R7 is not H;
in Formula VIII,
when Y and/or Yxe2x80x2 is substituted alkyl, arylamide or COOR, and R1 and R2 comprise 6,7-dimethyl or 5,6-dihydroxy, then at least one of R4, R5 and R6 is not H; and
when Zxe2x80x2 is O, then at least one of R1, R2, R3, R4, R5, R6 and R7 is not H, and R1, R2 and R3 do not comprise 7-methoxy;
in Formula IX,
when Y and/or Yxe2x80x2 is substituted alkyl, arylamide or COOR, and R1 and R2 comprise 6,7-dimethyl or 5,6-dihydroxy, then at least one of R4, R5 and R6 is not H; and
when Z is OH or alkoxy, then at least one of R1, R2, R3, R4, R5 and R6 is not H, and R1, R2 and R3 do not comprise 7-methoxy;
in Formula X,
when Y is substituted alkyl, arylamide or COOR, and R1 and R2 comprise 6,7-dimethyl or 5,6-dihydroxy, then at least one of R4, R5 and R6 is not H;
when Z is H, then at least one of Y, Yxe2x80x2, R4, R5 and R6 is not H; and
when Z is OH, at least one of R1, R2, R3, R4, R5, R6 and R7 is not H and provided further that Z may be H in the case of compounds of Formula IX or Formula X.
Another aspect of the present invention relates to pharmaceutical compositions containing the compounds of Formulas I to X, which compositions are suitable for administration to animals, more preferably mammals, and most preferably humans.
In another aspect of the present invention, methods are disclosed for using the compounds of Formulas I to X for the treatment and/or prevention of inflammation, inflammatory diseases, immunologic diseases and other diseases mediated by TNF-alpha, IL-6, COX-2 and/or interleukin-10 (IL-10).